FDA Panel Resuscitates Rosiglitazone, Votes to Keep It on the Market

But Warning of CV Risk for Some Patient Populations Added to Label

By Wayne Kuznar

GAITHERSBURG, Md—Physicians will most likely still have rosiglitazone (Avandia) to prescribe for their patients with type 2 diabetes, but they should now expect the product labeling to include a warning about an increased risk of ischemic heart disease in certain patient subgroups.

At the end of July, an FDA advisory panel voted nearly unanimously to recommend that rosiglitazone remain on the market, but the panel also agreed nearly as strongly that it increases the risk of ischemic heart disease.

The Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted 22 to 1 in favor of rosiglitazone's continued marketing, even though the advisory panel voted 20 to 3 that rosiglitazone did indeed increase cardiac ischemic risk in patients with type 2 diabetes.

The FDA did not indicate what action would be taken based on the advice it received from the advisory panel, but it did say that additional language in the label was warranted. "We heard fairly clear recommendations that some additional labeling was needed, and I often heard the word 'warning,' but I did not uniformly hear the words 'boxed warning,'" said Robert J. Meyer, MD, director of the FDA's Office of Drug Evaluation II, Centerfor Drug Evaluation and Research (CDER). "I don't think that we can say without rigorous internal discussion whether it will be a boxed warning, contraindications, or what."

Gerald Dal Pan, MD, MPH (left), and Robert J. Meyer, MD(right), of the FDA advisory panel.

The increased cardiovascular (CV) risk with rosiglitazone was most apparent in 3 patient subgroups:

• Those also using insulin
• Those taking nitrates long-term
• Those taking angiotensin-converting-enzyme (ACE) inhibitors.

Clifford J. Rosen, MD, acting chair of the advisory committee, offered guidance for the continued use of rosiglitazone. "There are reasons not to use this drug in certain type 2 diabetic patients," he said. "Those indications will likely fall under people who have congestive heart failure or are prone to congestive heart failure, those who have significant cardiovascular disease, particularly if they have been hospitalized previously for myocardial infarction, and I would be concerned about 2 other groups: the groups constantly using nitrates?and long-term users of insulin, who probably have advanced disease." He continued, "Clinicians will have to think twice before they prescribe this drug. Indeed, there are medications that may be safer in this situation." As one example, he said that "the use of this drug is probably not needed in patients on insulin."

The increased risk associated with rosiglitazone in insulin users and long-term users of nitrates was discovered in an FDA review of trials submitted by GlaxoSmithKline, the drug's manufacturer. In the FDA's own meta-analysis of 42 controlled, randomized clinical trials of patients with type 2 diabetes, a 40% increased risk (P = .02) of nonserious or serious myocardial ischemic events was observed with rosiglitazone.

The interaction between rosiglitazone and ACE inhibitors was discovered in an analysis of DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medications), which showed that congestive heart failure was 8 times more likely in patients using an ACE inhibitor?rosiglitazone combination compared with an ACE inhibitor only and 4 times as likely compared with rosiglitazone alone.

Rosiglitazone's most outspoken critic on the FDA panel was David Graham, MD, MPH, associate director for science and medicine, Office of Surveillance and Epidemiology at the FDA CDER. He indicated that the available data show a 70% increased risk of serious ischemic heart disease events compared with placebo. This and the lack of any unique benefit of the drug, he argued, render the marketing of rosiglitazone not justified.

Preliminary unpublished data from a meta-analysis comparing pioglitazone (Actos) and rosiglitazone were also presented by the CDER, which showed a significant reduction in the adjusted risk of myocardial infarction (MI) with pioglitazone compared with rosiglitazone (hazard ratio, 0.78; 95% confidence interval, 0.63-0.96). Dr Graham also discussed a study in which pioglitazone was associated with a strong trend (hazard ratio, 0.75; 95% confidence interval, 0.55-1.02) toward a reduction in all-cause death, nonfatal MI, or nonfatal stroke versus placebo.

The pioglitazone data were too new for a thorough review by the FDA before the advisory meeting, but many at the FDA believe that these data were too important to withhold. Gerald Del Pan, MD, MPH, director, FDA/CDER Office of Surveillance and Epidemiology, said, "The pioglitazone data were clinically relevant to the issue, so we presented it, with the caveat that they have to undergo FDA review."

IMWR

For those looking to trials in progress to provide definitive answers about rosiglitazone's CV safety, Dr Graham said that these trials "won't give us the clarity" because of design shortcomings. RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes) is one such trial (see , August 2007).

Most members of the advisory panel recommended that a warning about the increased risk of ischemic heart disease in the subgroups taking nitrates long-term, ACE inhibitors, or insulin long-term should be included in rosiglitazone's labeling.